DESCRIPTION: (Applicant's Abstract) Ensembles of neurons in the rat hippocampus and subiculum demonstrate changes in firing that correlate to the encoding of task and trial-specific information, and the recognition or recall of this information at later phases of a delayed-nonmatch-to-sample (DNMS) task. Error trials occur either when that information cannot be recalled, or when the information is recalled at an inappropriate time. In the absence of the hippocampus (i.e., following lesions) appropriate recall is impaired, although the animals are otherwise able to perform the task. Inappropriate recall (proactive interference) take the form of a sequential dependency in which the current neural activity (and behavior) is modified as a function of previous events within the task. Administration of cannabinoid receptor agonists (delta-9-THC and WIN 55,212-2) have shown a selective impairment of the encoding phase, but not the recognition phase, and in fact, an increase in the inappropriate recall of information. The selective effect of cannabinoids suggests that two separate neural circuits are involved in the processing of DNMS task information: an encoding circuit, from entorhinal cortex to hippocampus and back via dentate gyrus, CA3 and CA1 cell fields and subiculum; and a recall circuit involving projections directly from entorhinal cortex to CAT. The presence of cannabinoid receptors primarily on cells in the encoding pathway suggests that endogenous cannabinoid ligand may play an essential role in the normal maintenance of serial memory. This project will further define the characteristics of neural activity in subiculum and entorhinal cortex during DNMS behavior. The role of these areas in serial memory will be explored via lesions of subiculum and entorhinal cortex, and the susceptibility to disruption by cannabinoids will be determined by recording ensemble activity and behavioral responses to cannabinoids in both intact and lesioned animals. These experiments will further elucidate the neural circuitry underlying serial memory, as well as the role of endogenous cannabinoids in maintaining this memory.